Central nervous system (CNS) HIV infections can cause severe problems such as AIDS-related dementia. The brain, however, excludes many active anti-HIV drugs because of the blood brain-barrier (BBB). The objective of this project is the design, synthesis and anti-HIV evaluation of prodrugs with improved CNS transport properties. F-ddA, a LMCH drug in the final stages of a NCI Phase I clinical trial, is being used as a prototype prodrug in an evolving mathematical model designed to choose an optimum CNS candidate from among a group of 16 new compounds synthesized for that purpose. These compounds can be enzymatically hydrolyzed by adenosine deaminase (ADA) to F-ddI, an anti-HIV-active compound. Compound properties (lipophilicity, acid-stability) determine BBB penetration, with ADA-catalyzed hydrolysis in the CNS generating the active material (F-ddI). Rat tissue distribution data for these compounds are being generated for correlation with compound properties in a physiologic-based mathematical model. In addition, more efficient methods for 2'-fluoronucleoside synthesis are being investigated based on newly discovered chemistry. AIDS title:"Fluoronucleosides as CNS-Targeted Anti-Aids Drugs"